Behavioral and neuroendocrine reactivity to stress in the WKHA/WKY inbred rat strains: a multifactorial and genetic analysis

Genetic factors have been shown to influence the nature and the intensity of the stress responses. In order to understand better the genetic mechanisms involved, we have studied the behavioral and neuroendocrine responses to novel environments in the WKHA/WKY inbred strains and we have investigated the genetic relationships between these traits in a segregating F2 intercross. The animals were submitted to behavioral tests known to provide both indices of activity and fear (activity cages, open field and elevated plus-maze). The plasma levels of prolactin, ACTH, corticosterone, glucose and renin activity were determined after a 10-min exposure to novelty. Our results showed that WKHA rats, compared to WKYs, were more active in a familiar as well as in novel environments. They exhibited also less anxiety-related behaviors and lower neuroendocrine responses. A principal component analysis performed on the behavioral F2 results defined three independent factors: general activity, anxiety and defecation, none of them being correlated with the neuroendocrine measures. Thus this study suggests that these different responses to stress are independent components that may have distinct molecular bases.     

The factor structure of posttraumatic stress disorder: a literature update, critique of methodology, and agenda for future research

We present an update of recent literature (since 2007) exploring the factor structure of posttraumatic stress disorder (PTSD) symptom measures. Research supporting a four-factor emotional numbing model and a four-factor dysphoria model is presented, with these models fitting better than all other models examined. Variables accounting for factor structure differences are reviewed, including PTSD query instructions, type of PTSD measure, extent of trauma exposure, ethnicity, and timing of administration. Methodological and statistical limitations with recent studies are presented. Finally, a research agenda and recommendations are offered to push this research area forward, including suggestions to validate PTSD's factors against external measures of psychopathology, test moderators of factor structure, and examine heterogeneity of symptom presentations based on factor structure examination.     

Child Adjustment and Parent Efficacy Scale-Developmental Disability (CAPES-DD): First psychometric evaluation of a new child and parenting assessment tool for children with a developmental disability

This study examined the psychometric properties of the Child Adjustment and Parent Efficacy Scale-Developmental Disability (CAPES-DD), a brief inventory for assessing emotional and behavioral problems of children with developmental disabilities aged 2- to 16-years, as well as caregivers’ self-efficacy in managing these problems. A sample of 636 parents participated in the study. Children's ages ranged from 2 to 15. Exploratory and confirmatory factor analyses supported a 21-item, three-factor model of CAPES-DD child adjustment with 13 items describing behavioral (10 items) and emotional (3 items) problems and 8 items describing prosocial behavior. Three additional items were included due to their clinical usefulness and contributed to a Total Problem Score. Factor analyses also supported a 16-item, one factor model of CAPES-DD self-efficacy. Psychometric evaluation of the CAPES-DD revealed scales had satisfactory to very good internal consistency, as well as very good convergent and predictive validity. The instrument is to be in the public domain and free for practitioners and researchers to use. Potential uses of the measure and implications for future validation studies are discussed.     

Plasma corticosterone, dexamethasone (DEX) suppression and DEX/CRH tests in a rat model of genetic vulnerability to depression

The hypothalamo-pituitary-adrenal (HPA) axis is hyperactive in major depressive disorder (MDD), and baseline cortisol levels are usually elevated in MDD patients, with alterations of the circadian hormone secretion pattern. The dexamethasone (DEX) suppression test (DST) has been extensively applied to diagnose a dysregulation of the HPA axis in MDD, but it has only a limited sensitivity to, and specificity for, depression. The DEX/CRH test, which combines the DST with a corticotropin-releasing hormone (CRH) challenge, has proved more reliable to show HPA axis dysfunction in MDD. We have applied these two tests to a putative model of vulnerability to depression in rodents, the Roman high-(RHA) and low-(RLA) Avoidance rat lines. As compared to RHA, RLA rats are behaviorally inhibited, they show an exaggerated response of the HPA axis to stress, and are more prone to develop depressive-like features when exposed to chronic stress. Our results show that (a) there were no significant differences in circadian plasma corticosterone (CORT) levels and/or secretion patterns between the two lines; (b) in the DST test, CORT was suppressed to the same extent in RHA and RLA rats; and c) in the DEX/CRH test, areas-under-the-curve (AUCs) and CORT delta (peak minus baseline) responses were significantly larger in RLA rats. One possible interpretation of these data is that an increased response to CRH could be a trait marker (or endophenotype) for depression, whereas alterations of circadian glucocorticoid secretion patterns and non-suppression of the daily glucocorticoid rise by dexamethasone could be state markers, i.e. features that are only present during depressive episodes.     

Adolescents with a history of specific language impairment (SLI): Strengths and difficulties in social,emotional and behavioral functioning

Adolescents with specific language impairment (SLI) are at a greater risk of emotional and behavioral problems compared to their typically developing (TD) peers, but little is known about their self-perceived strengths and difficulties. In this study, the self-reported social, emotional and behavioral functioning of 139 adolescents with a history of SLI and 124 TD individuals at age 16 was examined. The self-report version of the Strengths and Difficulties Questionnaire (SDQ) was used to assess their prosocial behavior and levels of peer, emotional and behavioral difficulties. Associations of these areas of functioning with gender, verbal and non-verbal skills were also investigated. Adolescents with a history of SLI were more likely than their TD peers to report higher levels of peer problems, emotional symptoms, hyperactivity and conduct problems. The majority of adolescents in both groups (87% SLI and 96% TD), however, reported prosocial behavior within the typical range. Difficulty with peer relations was the strongest differentiator between the groups, with the odds of reporting borderline or abnormally high levels of peer problems being 12 times higher for individuals with a history of SLI. Adolescents with poorer receptive language skills were also more likely to report higher levels of emotional and behavioral difficulties. The findings of this study identify likely traits that may lead to referral to services.     

Confirmatory factor analysis and item response theory analysis of the Whiteley Index. Results from a large population based study in Norway. The Hordaland Health Study (HUSK)

Objective

The Whiteley Index (WI) is a widely used screening instrument for health anxiety/hypochondriasis. Several studies have previously explored the psychometric properties of the WI, but with mixed findings concerning both item composition and factor structure. The main aim of the current study was to examine different factor structures as identified from previous studies using data from a large general population based study. We also wanted to provide gender specific norms.

Methods

Data were taken from a large population-based study in Norway, the Hordaland Health Study (HUSK N = 7274). Confirmatory factor analysis (CFA) of several models of the WI was conducted. Item response theory (IRT) analysis was performed on the model with the best goodness-of-fit.

Results

CFA of all previously proposed factor models of the WI revealed clearly inadequate model fits. The IRT analysis suggested that a six-item model best described the data, and CFA confirmed an adequate goodness-of-fit across indices.

Conclusion

The current study found evidence for a six-item, single-factor model of the WI. Our findings suggest that this abbreviated version has the best factor structure compared to previously proposed factor models. We recommend that the factor structure identified in this study should be investigated further in independent samples.     

Brain mapping of the gonadotropin-inhibitory hormone-related peptide 2 with a novel antibody suggests a connection with emotional reactivity in the Japanese quail (Coturnix japonica,Temminck & Schlegel, 1849)

Gonadotropin-inhibitory hormone (GnIH) is a neuropeptide first discovered in the quail brain that is involved in the control of reproductive physiology and behaviors, and stress response. GnIH gene encodes a second peptide, GnIH-related peptide-2 (RP2), the distribution and function of which remain unknown. We therefore studied GnIH-RP2 distribution by immunohistochemistry using a novel antibody capable of discriminating between GnIH and GnIH-RP2. The overall distribution of GnIH-RP2 is similar to that of GnIH. The vast majority of labeled neurons is located in the paraventricular nucleus (PVN) of the hypothalamus. Labeling of fibers is conspicuous in the diencephalon, but present also in the mesencephalon and telencephalon. Several regions involved in the control of reproduction and stress response (the PVN, septum, bed nucleus of the stria terminalis and nucleus commissura pallii) showed a dense network of immunolabeled fibers. To investigate the potential function of GnIH-RP2 we compared its expression in two quail lines genetically selected for divergence in their emotional reactivity. A quantitative analysis in the above-mentioned brain regions showed that the density of fibers was similar in the two lines. However, the number of GnIH-RP2 labeled neurons was higher in the median portion of the PVN in birds with higher emotional reactivity. These results point to a possible involvement of GnRH-RP2 in modulating stress response and/or emotional reactivity.     

Short-term effect of cigarette smoking on CO(2)-induced vasomotor reactivity in man: a study with near-infrared spectroscopy and tanscranial Doppler sonography

Cigarette smoking is a major risk factor for stroke, and quitting reduces the stroke risk within a few years. The aim of our study was to clarify whether CO(2)-induced vasomotor reactivity (VMR) is impaired in smokers after smoking a cigarette as a possible factor of an increased stroke risk. We compared VMR of 23 healthy smokers assessed at baseline, immediately, and 30 min after smoking a cigarette (1.2 mg nicotine) with values from nonsmoking, age-matched controls (n=24), obtained at identical time intervals. Cerebral blood flow velocities (CBFV) of both middle cerebral arteries (transcranial Doppler sonography), changes in concentration of cerebral oxygenated, deoxygenated, and total hemoglobin (HbO(2), Hb, and HbT, near-infrared spectroscopy), mean arterial blood pressure (MAP), and skin blood flow were recorded during normo- and hypercapnia. VMR was calculated as percentage change in CBFV and as micromolar change in concentration of HbO(2), Hb, and HbT per 1% increase in endtidal CO(2). CBFV in smokers was increased at baseline (left, p<0.05; right, p=0.05), immediately (p<0.01), and 30 min after smoking (p<0.05) as compared with nonsmokers. MAP rose immediately after smoking (p<0.01) and declined after 30 min. VMR in smokers at baseline did not differ from controls, decreased immediately after smoking (p<0.05), and normalized after 30 min (p>0.05). Increased baseline CBFV in smokers after smoking might be due to arteriolar dilation, increased MAP, and possibly constriction of basal cerebral arteries. Impaired VMR for about 30 min after smoking reflects endothelial dysfunction. This might contribute to the enhanced stroke risk in smokers.     

Detailed distribution of neuropeptide FF receptors (NPFF1 and NPFF2) in the rat, mouse, octodon, rabbit, guinea pig, and marmoset monkey brains: a comparative autoradiographic study

The distribution of neuropeptide FF receptors (NPFF(1) and NPFF(2)) was analyzed throughout the central nervous system of rodents (rat, mouse, Octodon degus, and guinea pig), rabbit, and marmoset monkey brains, representing three orders of mammals. Quantitative in vitro receptor autoradiography with [(125)I]EYF ([(125)I]EYWSLAAPQRF-NH(2)) and [(125)I]YVP ([(125)I]YVPNLPQRF-NH(2)) as specific radioligands for NPFF(2) and NPFF(1) receptors, respectively, was used. The NPFF(2) receptor is predominantly expressed in all species, except in the central nervous system of Octodon degus, in which it is undetectable. The density of the NPFF(1) subtype is low in rat and mice, moderate in octodon, rabbit, and monkey, and relatively high in the guinea pig. The present study reveals prominent species differences in the NPFF receptors expression in the brain. The distribution pattern of NPFF(2) receptors in the diencephalon and the superficial layers of the spinal cord is consistent with a hypothesized potential role for NPFF in the modulation of sensory input and opioid analgesia. In contrast, the constant presence of NPFF(1) receptors in the septum, the nucleus of the tractus solitarius, and the hypothalamus suggest its participation in neuroendocrine functions.     

Efficacy and safety of olorinab,a full agonist of the cannabinoid receptor 2, for the treatment of abdominal pain in patients with irritable bowel syndrome: Results from a phase 2b randomized placebo-controlled trial (CAPTIVATE)

Background

Olorinab is a highly selective, peripherally acting, full agonist of cannabinoid receptor 2. This study assessed the efficacy and safety of olorinab to treat abdominal pain in patients with irritable bowel syndrome with diarrhea (IBS-D) and constipation (IBS-C).

Methods

CAPTIVATE was a phase 2b, randomized, double-blind, placebo-controlled, parallel-group trial. Eligible participants aged 18–70 years with IBS-C and IBS-D diagnosed per Rome IV received olorinab 10 mg, 25 mg, or 50 mg three times daily (TID) or placebo TID for 12 weeks. The primary endpoint was the change in patient-reported average abdominal pain score (AAPS) from baseline to Week 12.

Key Results

A total of 273 participants were randomized to receive olorinab 10 mg (n = 67), olorinab 25 mg (n = 67), olorinab 50 mg (n = 69), or placebo (n = 70). Although a treatment response was observed across all groups, the weekly change in average AAPS from baseline to Week 12 was not significantly different between placebo and any olorinab dose. In a prespecified subgroup analysis of participants with a baseline AAPS ≥6.5, olorinab 50 mg (n = 35) significantly improved AAPS compared with placebo (n = 30) (p = 0.014). Adverse event rates were comparable between olorinab and placebo and there were no reported serious adverse events or deaths.

Conclusion and Inferences

Although olorinab was well-tolerated and improved weekly AAPS, the primary endpoint was not met. However, in participants with moderate-to-severe pain at baseline (AAPS ≥6.5), olorinab 50 mg significantly improved weekly AAPS compared with placebo. ClinicalTrials.gov : NCT04043455.     

Generalized autoimmunity of the nervous system (GANS) induced by a recombinant protein composed of major pathogenic determinants of MBP,IRBP, and P2 protein: Suppression of inflammation by a monoclonal antibody against activated rat T line cells

We have developed a new model of generalized autoimmunity of the rat nervous system to study differential immunoregulation, barrier-function, and parenchymal inflammatory processes. We designed a multicomponent synthetic gene encoding major pathogenic determinants for Lewis rats of myelin basic protein (MBP), interphotoreceptor retinoid binding protein (IRBP), and P₂ protein. Immunization with the recombinant protein induces a monophasic disease with inflammatory lesions in the eye, brain, spinal cord, and peripheral nerves. Rats recovered from GANS were tolerant against the induction of experimental autoimmune encephalomyelitis (EAE), neuritis (EAN), and uveoretinitis (EAU) by immunization with synthetic autoantigen-peptides/CFA. To demonstrate an application of GANS we have used a monoclonal antibody raised against encephalitogenic rat T lymphocytes. We show that this monoclonal antibody is suppressing not only inflammatory cell infiltration of brain and spinal cord, but as well of the eyes and the peripheral nervous system. © 1996 Wiley-Liss, Inc.